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Background: To determine the prevalence and risk factors of epiretinal membrane (ERM) utilising spectral‐domain optical coherence tomography (SD‐OCT). Methods: We investigated data from the 2017 to 2018 Korea National Health and Nutrition Examination Survey. Individuals aged ≥40 years with readable fundus photographs and SD‐OCT results were included. ERM was diagnosed by fundus photography and OCT. The following data was collected: demographics, health interview, health examination, and nutritional survey results. The prevalence of ERM was estimated and risk factors for ERM were analysed. Results: A total of 6807 participants were finally included. Adjusted prevalence of ERM was 7.0% (95% confidence interval, 6.3%–7.8%). Multivariate logistic regression analysis revealed that age ≥ 50 years (p < 0.001 for all age groups), history of cataract surgery (p < 0.001), well‐controlled hypertension (p = 0.006), and diabetic retinopathy (p = 0.041) were risk factors for ERM. Conclusions: The estimated prevalence of ERM was 7.0%, which was higher than that of previous reports using fundus photography only in an East Asian population. Possible risk factors for ERM were older age, history of cataract surgery, hypertension, and diabetic retinopathy. [ABSTRACT FROM AUTHOR]

Introduction/Aims: Intraneural ganglion cysts (INGCs) are non‐neoplastic mucinous cysts within the epineurium of peripheral nerves. Characteristics of INGCs around the hip joint have not been adequately described. We aimed to describe clinical features, imaging findings, and treatment outcomes in patients with INGCs originating from the hip joint. Methods: We retrospectively included cystic lesions around the hip joint satisfying the following inclusion criteria over 6 years: (1) multilocular elongated hyperintense cystic mass on T2‐weighted imaging; and (2) distribution along the course of the peripheral nerve and its branches on magnetic resonance imaging (MRI). Results: Six patients with an INGC around the hip joint were identified. Parent peripheral nerves were the sciatic nerve (four patients), the superior gluteal nerve (one patient), and the nerve to quadratus femoris (one patient). Buttock, groin, or lower extremity pain/paresthesias were the initial symptoms in all patients. INGCs within the articular branches of the hip joint were identified on MRI. Four patients underwent arthroscopic debridement and capsulotomy. All patients showed generally favorable outcome regardless of treatment. Discussion: Physicians should consider the possibility of INGCs originating from the hip joint as a cause of nontraumatic hip, buttock, or lower extremity pain. This can occur in any nerve innervating the hip joint, and usually it originates in the posterior capsule of the hip joint. Arthroscopic surgery shows promising results; however, more information about the surgical technique and long‐term follow‐up results are needed. See Editorial on pages 236‐239 in this issue [ABSTRACT FROM AUTHOR]

Three‐dimensional (3‐D) analysis of human epidermal melanocytes is required for deeper understanding of melanocytic disorders. The purpose of this study was to standardize 3‐D imaging and quantification for the evaluation of epidermal melanocytes. The epidermal specimen was obtained using the suction blister method from a patient with melanocytic nevus on the forearm skin. Cutaneous ACT‐PRESTO, the tissue‐clearing and labeling technique, was subsequently performed. With the 3‐D image analysis program, morphological reconstruction and quantification of selected perilesional and melanocytic nevus areas were possible. The region of melanocytic nevus showed higher numbers of total melanocytic dendrites and similar numbers of cell bodies compared with perilesional area. In addition, the mean area and volume of cell bodies increased in the melanocytic nevus area compared with the results in the perilesional area. The 3‐D evaluation method of human epidermal melanocytes can be applied to investigate novel pathologies related to hyper‐ or hypo‐pigmentary disorders. [ABSTRACT FROM AUTHOR]

The two members of the cytoplasmic FMR1‐interacting protein family, CYFIP1 and CYFIP2, are evolutionarily conserved multifunctional proteins whose defects are associated with distinct types of brain disorders. Even with high sequence homology between CYFIP1 and CYFIP2, several lines of evidence indicate their different functions in the brain; however, the underlying mechanisms remain largely unknown. Here, we performed reciprocal immunoprecipitation experiments using CYFIP1‐2 × Myc and CYFIP2‐3 × Flag knock‐in mice and found that CYFIP1 and CYFIP2 are not significantly co‐immunoprecipitated with each other in the knock‐in brains compared with negative control wild‐type (WT) brains. Moreover, CYFIP1 and CYFIP2 showed different size distributions by size‐exclusion chromatography of WT mouse brains. Specifically, mass spectrometry‐based analysis of CYFIP1‐2 × Myc knock‐in brains identified 131 proteins in the CYFIP1 interactome. Comparison of the CYFIP1 interactome with the previously identified brain region‐ and age‐matched CYFIP2 interactome, consisting of 140 proteins, revealed only eight common proteins. Investigations using single‐cell RNA‐sequencing databases suggested non‐neuronal cell‐ and neuron‐enriched expression of Cyfip1 and Cyfip2, respectively. At the protein level, CYFIP1 was detected in both neurons and astrocytes, while CYFIP2 was detected only in neurons, suggesting the predominant expression of CYFIP1 in astrocytes. Bioinformatic characterization of the CYFIP1 interactome, and co‐expression analysis of Cyfip1 with astrocytic genes, commonly linked CYFIP1 with focal adhesion proteins. Immunocytochemical analysis and proximity ligation assay suggested partial co‐localization of CYFIP1 and focal adhesion proteins in cultured astrocytes. Together, these results suggest a CYFIP1‐specific association with astrocytic focal adhesion, which may contribute to the different brain functions and dysfunctions of CYFIP1 and CYFIP2. Cover Image for this issue: https://doi.org/10.1111/jnc.15410 [ABSTRACT FROM AUTHOR]

Wheatgrass and barley grass are freshly sprouted leaves of wheat and barley seeds and are rich sources of phytochemicals. This study was conducted to investigate the effects of drought stress on the biochemical compounds and antioxidant activities of barley grass and wheatgrass extracts. The grass was cultivated in an organic soil growing medium with different levels of drought stress (a control with 100% water holding capacity (WHC), mild drought stress with 75% WHC, moderate drought stress with 50% WHC, and severe drought stress with 25% WHC) in a growth chamber by controlling temperature (20/15 °C, day/night), light (12/12 h, light/dark; intensity 150 μmol m−2 s−1 with quantum dot light‐emitting diodes), and relative humidity (60%) for 7 days. The drought stress showed increased levels of biochemical compounds, especially phenolics, flavonoids, and vitamin C, in both barley grass and wheatgrass extracts. The wheatgrass extracts showed 1.38–1.67 times higher phenolics, flavonoids, and vitamin C contents than the barley grass extracts did. The antioxidant (2,2′‐azino‐bis(3‐ethylbenzothiazoline‐6‐sulfonic acid), 2,2‐diphenyl‐1‐picrylhydrazyl radical‐scavenging activity, and nitrite‐scavenging activity) and antioxidant enzymes (guaiacol peroxidase, catalase, and glutathione reductase) were the highest under severe drought stress in both barley grass and wheatgrass extracts; and the wheatgrass extracts showed 1.20–5.70 times higher antioxidant enzyme activities than the barley grass extracts did. Proper drought‐stress treatment of barley grass and wheatgrass may be a convenient and efficient method to increase biochemical compounds and antioxidants in our diet to exploit the related health benefits. © 2021 Society of Chemical Industry. [ABSTRACT FROM AUTHOR]

Aim: To investigate the role of autophagy in MTA‐induced odontoblastic differentiation of human dental pulp cells (HDPCs). Methodology: In MTA‐treated HDPCs, odontoblastic differentiation was assessed based on expression levels of dentine sialophosphoprotein (DSPP) and dentine matrix protein 1 (DMP1), alkaline phosphatase activity (ALP) activity by ALP staining and the formation of mineralized nodule by Alizarin red S staining. Expression of microtubule‐associated protein 1A/1B‐light chain3 (LC3), adenosine monophosphate‐activated protein kinase (AMPK)/mammalian target of rapamycin (mTOR) signalling molecules and autophagy‐related genes was analysed by Western blot analysis and Acridine orange staining was used to detect autophagic lysosome. For in vivo experiments, tooth cavity preparation models on rat molars were established and the expression of proteins‐related odontogenesis and autophagy markers was observed by Immunohistochemistry and Western blot analysis. Kruskal–Wallis with Dunn's multiple comparison was used for statistical analysis. Results: Mineral trioxide aggregate (MTA) promoted odontoblastic differentiation of HDPCs, accompanied by autophagy induction, including formation of autophagic lysosome and cleavage of LC3 to LC3II (P < 0.05). Conversely, inhibition of autophagy through 3MA significantly attenuated the expression level of DSPP (P < 0.05) and DMP1 (P < 0.05) as well as formation of mineralized nodules (P < 0.05), indicating the functional significance of autophagy in MTA‐induced odontoblastic differentiation. Also, MTA increased the activity of AMPK (P < 0.01), whereas inhibition of AMPK by compound C downregulated DSPP (P < 0.01) and DMP1 (P < 0.05), but increased the phosphorylation of mTOR (P < 0.05), p70S6 (P < 0.01) and Unc‐51‐like kinases 1 (ULK1) (ser757) (P < 0.01), explaining the involvement of AMPK pathway in MTA‐induced odontoblast differentiation. In vivo study, MTA treatment after tooth cavity preparation on rat molars upregulated DMP‐1 and DSPP as well as autophagy‐related proteins LC3II and p62, and enhanced the phosphorylation of AMPK. Conclusion: MTA induced odontoblastic differentiation and mineralization by modulating autophagy with AMPK activation in HDPCs. Autophagy regulation is a new insight on regenerative endodontic therapy using MTA treatment. [ABSTRACT FROM AUTHOR]

The objective of this study was to evaluate the association between sodium intake and blood pressure (BP) control in hypertensive patients taking antihypertensive medications by using 24-hour urine collection and 24-hour ambulatory BP. This is a cross-sectional community-based study and conducted in 2011 and 2012. A total of 1128 participants were recruited from five cities in Korea. Among them, 740 participants who had complete 24-hour urine collection and valid 24-hour ambulatory BP data were included in this study. Participants were divided into four groups: normotensives (NT, n = 441), untreated hypertensive patients (UTHT, n = 174), controlled hypertensive patients (CHT, n = 62), and uncontrolled hypertensive patients (UCHT, n = 63). UCHT and CHT groups showed higher mean age than NT and UTHT groups. UCHT and UTHT groups showed higher 24-hour systolic BP (SBP) and diastolic BP (DBP) than NT and CHT groups. UCHT group had the highest level of 24-hour urine sodium. Multivariate analysis adjusted with age, gender, body mass index, estimated glomerular filtration rate, and use of diuretics showed higher level of 24-hour urine sodium in UCHT group than that in CHT group. Multivariate logistic regression analysis revealed independent association of the amount of 24-hour urine sodium with uncontrolled BP in hypertensive patients on antihypertensive drug treatment. Higher level of 24-hour urine sodium excretion in uncontrolled hypertensive patients suggests that excessive sodium intake could be associated with blunted BP lowering efficacy of antihypertensive medications. [ABSTRACT FROM AUTHOR]

Background and Aim: As the prevalence of nonalcoholic fatty liver disease (NAFLD) is increasing globally, patients with both NAFLD and chronic hepatitis B (CHB)‐related hepatocellular carcinoma (HCC) is also frequently found. This study aimed to investigate the clinical impact of concurrent NAFLD on the prognosis of patients with CHB‐related HCC. Methods: Patients with CHB‐related HCC who underwent surgical resection were consecutively selected from August 2009 to December 2013. The association between histologically proven concurrent NAFLD and clinical outcomes were analyzed. Propensity score (PS) matching was adapted to adjust for baseline characteristics. We also investigated the presence of nonalcoholic steatohepatitis (NASH) among patients with NAFLD and its association with clinical outcomes. Results: Among 338 CHB‐related HCC patients selected, 196 patients (58.0%) were diagnosed with concurrent NAFLD. The median follow‐up duration was 74.9 months. The patients with NAFLD tended to have better recurrence‐free survival (RFS; log‐rank, P = 0.16) and had significantly better overall survival (OS; log‐rank, P = 0.004) than those without NAFLD. However, the survival benefit of the concurrent NAFLD was not significant in a multivariable Cox analysis (adjusted hazard ratio, 0.94; 95% confidence interval, 0.51–1.73, P = 0.84) or an analysis after PS matching (log‐rank, P = 0.57). Regarding the presence or absence of NASH, no differences in the RFS (log‐rank, P = 0.61) and OS (log‐rank, P = 0.26) were found. Conclusions: Concurrent NAFLD was not associated with both RFS and OS in patients with CHB‐related HCC after adjusting for baseline characteristics. Moreover, NAFLD patients with NASH did not have significantly different clinical outcomes compared with NAFLD patients without NASH. [ABSTRACT FROM AUTHOR]

The authors developed an equation to estimate 24-hour urine sodium (24HUNa) using the average of three spot urine (SU) samples (morning-first, morning, and evening) from 74 individuals and validated this equation using the average of three SU samples (morning-first, daytime, and evening) from 174 additional individuals. Compared with previously published equations using a single SU sample, the currently developed equation using the average of three SU samples showed much lower bias from measured 24HUNa (-2.9 vs >10 mmol/24 h). The intraclass and concordance correlation coefficients of the proposed equation using the average of three SU samples were 0.909 and 0.832, respectively. The limits of agreement were -64.1-58.3 mmol/24 h and approximately 100 mmol/24 h for the currently developed and previously published equations, respectively. All equations showed a tendency to overestimate or underestimate 24HUNa in a manner dependent on the level of 24HUNa but irrespective of the number of SU samples considered. Nonetheless, among the currently tested equations, our equation using the average of three SU samples provided the best estimation of 24HUNa at a population level. [ABSTRACT FROM AUTHOR]

Background & Aims: There is no proven treatment for ursodeoxycholic acid (UDCA)‐refractory primary biliary cholangitis (PBC) other than obeticholic acid. Although fibrates have been reported to improve biochemical parameters, the long‐term effects remain unclear. This study evaluated the effect of fibrate on clinical outcomes of UDCA‐refractory PBC. Methods: Patients whose alkaline phosphatase (ALP) was not normalized with at least 13 mg/kg of UDCA treatment for >1 year were included from two tertiary referral centres. The primary outcome was ALP normalization. Secondary outcomes included the development of cirrhosis and hepatic deterioration. Immortal time bias was adjusted using the Mantel‐Byar method. Results: A total of 100 UDCA‐refractory PBC patients were included: 71 patients received UDCA alone (the UDCA group) and 29 patients received UDCA plus additional fibrate treatment of 160 mg/d fenofibrate or 400 mg/d bezafibrate (the fibrate/UDCA group). During the follow‐up period, the probability of ALP normalization was significantly higher in the fibrate/UDCA group (hazard ratio [HR] = 5.00, 95% confidence interval = 2.87‐8.27, P < 0.001). Among 58 non‐cirrhotic patients (43 in the UDCA group and 15 in the fibrate/UDCA group), 19 patients (44.1%) in the UDCA group and none in the fibrate/UDCA group developed cirrhosis (HR = 0.12, P = 0.04). Hepatic deterioration (Child‐Pugh score increase or signs of decompensated cirrhosis) occurred in 17 patients (23.9%) of the UDCA group and none in the fibrate/UDCA group in which the difference was significant (HR = 0.12, P = 0.04). Conclusions: In patients with UDCA‐refractory PBC, additional fibrate treatment is associated with a higher probability of ALP normalization and a lower risk of cirrhosis development and hepatic deterioration. [ABSTRACT FROM AUTHOR]

Three‐dimensional microscopy provides more extended depth of penetration compared with conventional light microscopy and is known to be useful in clinical evaluation of thick biological specimens. Skin nerve biopsy together with the quantification of intraepidermal nerve fibers in multiple thick sections has been widely adopted for evaluating peripheral neuropathies. The aim of the present study was to evaluate the effectivity of three‐dimensional microscopy in reducing the required time and inter‐rater discrepancies, especially in the case of personnel not familiar with the quantification methods. A total of six cryo‐sectioned specimens were analyzed for the study and the skin samples were collected from one patient with postherpetic neuralgia who voluntarily participated in the study. Two investigators, a physician and non‐physician assessed the intraepidermal nerve fiber densities and required analysis time using three different methods including direct visualization of tissue slides, and analysis with two‐ and three‐dimensional images. Three‐dimensional microscopy could produce images that enabled reliable evaluation of intraepidermal nerve fibers; the accuracy of analysis was statistically comparable between the physician and non‐physician (p > .05). Three‐dimensional microscopy also enabled the non‐physician to proceed meaningfully faster evaluation compared with the direct visualization method (p = .03). Three‐dimensional microscopy could be one of the useful methods to improve accuracy and convenience of the analysis of intraepidermal nerve fibers especially appropriate for unaccustomed physician or non‐physician. Research Highlights: Three‐dimensional microscopy is capable of producing images with more extended depth of penetration compared with conventional light microscopy and has been known to be suitable for clinical evaluation of thick biological specimens. Cutaneous nerve biopsy and the quantification of nerve fibers in thick sections has been widely adopted for evaluating peripheral neuropathies. Three‐dimensional microscopy could be especially appropriate for unaccustomed physician or non‐physician to improve accuracy and convenience of the analysis of intraepidermal nerve fibers. Three dimensional images of cutaneous nerve fibers produced by 3D microscopy (50‐μm‐thick section, ×400). The image presents detailed course of intraepidermal nerve fibers which contribute to clear evaluation of investigators [ABSTRACT FROM AUTHOR]

FIGURE: Expression and stability of wild-type (WT) or mutant CYFIP2 in HEK293T cells or cultured neurons. Second, we examined protein levels of wild-type or mutant CYFIP2 by transfecting the constructs into HEK293T cells or cultured rat cortical neurons (Fig). [Extracted from the article]

Epidermal growth factor (EGF) is widely recognized to be involved in the regenerative process, but only a few studies document its effect on acute wounds when EGF release is sustained over a period of time by encapsulation in an emulsion-based hydrogel. Among hydrogels, hyaluronic acid (HA) is a promising carrier because it is biodegradable and known to bind to the components of the Extracellular Matrix (ECM) which undergoes remodeling during regeneration. Coupled with EGF in microparticulates, it may serve to directly deliver the cytokine to the impaired ECM to stimulate cells for ECM remodeling. In this study, a very simple and effective way is demonstrated to produce EGF-conjugated HA microspheres for the purpose of targeted and sustained EGF delivery to damaged ECM in acute wounds. This approach is advantageous due to its simplicity which may serve to accelerate research in wound regeneration and relevant drug discovery. [ABSTRACT FROM AUTHOR]

Nanofiber-based hydrocolloid scaffold is prepared by colloid electrospinning of thermoplastic polyurethane (TPU)/sodium carboxymethyl cellulose (S.CMC) in tetrahydrofuran (THF)/dimethylformamide (DMF). The most suitable process of electrospinning for successful formation of fibers is investigated by controlling the concentration of polymeric solution and co-solvent ratio. In order to accomplish high wettability, the amount of colloid (S.CMC) and the co-solvent ratio (THF/DMF), which affects the morphology of fibers, are adjusted. Finally, the open wound healing effect is confirmed using nanofiber-hydrocolloid from in vivo animal studies. A detailed study of the wound healing process is also demonstrated for the first time. [ABSTRACT FROM AUTHOR]

As wound contraction in the cutaneous layer occurs rapidly in mice, mechanical means are typically used to deliberately expose the wound to properly investigate healing by secondary intention. Previously, silicon rings and splinting models were attempted to analyze histological recovery but prevention of surrounding epidermal cell migration and subsequent closure was minimal. Here, we developed an ideal chimney wound model to evaluate epidermal regeneration in murine under hESC-EC transplantation through histological analysis encompassing the three phases of regeneration: migration, proliferation, and remodeling. Human embryonic stem cell derived endothelial cells (hESC-EC) were transplanted due to possessing a well-known therapeutic effect in angiogenesis which also enhances epidermal repair to depict the process of regeneration. Following a standard 1 mm biopsy punch, a chimney manufactured by modifying a 1.7 mL microtube was simply inserted into the excisional wound to complete the modeling process. Under this model, the excisional wound remained fully exposed for 14 days and even after 4 weeks, only a thin transparent layer of epidermal tissue covered the wound site. This approach is able to more accurately depict epidermal repair in relation to histology while also being a user-friendly and cost-effective way to mimic human recovery in rodents and evaluate epithelial repair induced by a form of therapy. [ABSTRACT FROM AUTHOR]

The article focuses on a study about creating a fabrication method for an extreme wetting on a polymer substrate by introducing the superhydrophilic seed layer concept which can be made by contact printing and photochemical oxidation with ultrathin low-molecular-weight (LMW) polydimethylsiloxane (PDMS) layer. Information about the low packing density with nanoroughness morphology of the LMW PDMS is presented.

Many stimulus-induced release systems have been studied for the smart control of drug delivery. Mechanical strain is rarely investigated as means of stimulation for these systems, despite the fact that there are many biological processes and human body motions that involve strain changes. In this study, a design for a stretchable reservoir-based patch-type release system is suggested. The reservoir made of an elastomer undergoes a decrease in volume when the system is deformed by bending and stretching. The response is predicted by finite element method modeling studies. The release rate of the reservoir is finely controlled by attaching elastic microchannels with different channel lengths. Because the whole system is made of rubber, the patch is deformable and the solution can be refilled with a microsyringe. Systematic designs for on/off release, long-term release, and short-term release are suggested. [ABSTRACT FROM AUTHOR]

The major limitations of nanocarriers for drug delivery are the poor biocompatibility and low stability that may induce the unintended burst release of loaded drugs during blood circulation. To overcome these limitations, a photocrosslinkable amphiphilic block copolymer consisting of hydrophobic poly(ε-caprolactone) (PCL) block and a hydrophilic hyperbranched polyglycerol (hbPG) block with improved biocompatibility and stability for drug delivery is developed. They are readily prepared via UV-triggered chemical crosslinking with 4-hydroxycinnamic acid (CA) modification in the hbPG block. The photocrosslinked hbPG- b-PCL-CA nanoparticles are spherical and the size of nanoparticles is increased to 60 ± 30 nm. Photocrosslinked hbPG- b-PCL-CA nanoparticles exhibit significantly high stability in a physiological buffer and the loaded drug in sustained manner. In addition, photocrosslinked hbPG- b-PCL-CA nanoparticles show good biocompatibility in vitro and in vivo. These data imply the promising potential of photocrosslinked hbPG- b-PCL-CA nanoparticles as nanocarriers for drug delivery. [ABSTRACT FROM AUTHOR]

The homeostatic regulation of neuronal activity in glutamatergic and GABAergic synapses is critical for neural circuit development and synaptic plasticity. The induced expression of the transcription factor early growth response 1 (Egr-1) in neurons is tightly associated with many forms of neuronal activity, but the underlying target genes in the brain remained to be elucidated. This study uses a quantitative real-time PCR approach, in combination with in vivo chromatin immunoprecipitation, and reveals that GABAA receptor subunit, GABRA2 (α2), GABRA4 (α4), and GABRQ (θ) genes, are transcriptional targets of Egr-1. Transfection of a construct that over-expresses Egr-1 in neuroblastoma (Neuro2A) cells up-regulates the α2, α4, and θ subunits. Given that Egr-1 knockout mice display less GABRA2, GABRA4, and GRBRQ mRNA in the hippocampus, and that Egr-1 directly binds to their promoters and induces mRNA expression, the present findings support a role for Egr-1 as a major regulator for altered GABAA receptor composition in homeostatic plasticity, in a glutamatergic activity-dependent manner. [ABSTRACT FROM AUTHOR]

In neuronal development, dendritic outgrowth and arborization are important for the establishment of neural circuit formation. A previous study reported that PSD-95-interacting regulator of spine morphogenesis (Preso) formed a complex with PAK-interacting exchange factor-beta (βPix) via PSD-95/Dlg/ZO-1 (PDZ) interaction. Here, we report that Preso and its binding protein, βPix, are localized in dendritic growth cones. Knockdown and dominant-negative inhibition of Preso in cultured neurons markedly reduced the dendritic outgrowth but not branching, and led to a decrease in the intensity of βPix and F-actin in neuronal dendritic tips. Moreover, phosphatidylinositol 4,5-bisphosphate (PIP2) induced a conformational change in Preso toward the open PDZ domain and enhanced the interaction with βPix. In addition, the Preso band 4.1 protein, ezrin, radixin and moesin (FERM) domain mutant is unable to interact with PIP2 and it did not rescue the Preso-knockdown effect. These results indicate that PIP2 is a key signalling molecule that regulates dendritic outgrowth through activation of small GTPase signalling via interaction between Preso and βPix. [ABSTRACT FROM AUTHOR]

In the last 10 years, many studies have reported that neural stem/progenitor cells spontaneously produce new neurons in a subset of adult brain regions, including the hippocampus, olfactory bulb (OB), cerebral cortex, substantia nigra, hypothalamus, white matter and amygdala in several mammalian species. Although adult neurogenesis in the hippocampus and OB has been clearly documented, its occurrence in other brain regions is controversial. In the present study, we identified a marked accumulation of new neurons in the subcallosal zone (SCZ) of Bax-knockout mice in which programmed cell death (PCD) of adult-generated hippocampal and OB neurons has been shown to be completely prevented. By contrast, in the SCZ of wild-type (WT) mice, only a few immature (but no mature) newly generated neurons were observed, suggesting that virtually all postnatally generated immature neurons in the SCZ were eliminated by Bax-dependent PCD. Treatment of 2-month-old WT mice with a caspase inhibitor, or with the neurotrophic factor brain-derived neurotrophic factor, promoted the survival of adult-generated neurons, suggesting that it is the absence of sufficient neurotrophic signaling in WT SCZ that triggers the Bax-dependent, apoptotic PCD of newly generated SCZ neurons. Furthermore, following focal traumatic brain injury to the posterior brain, SCZ neurogenesis in WT mice was increased, and a subset of these newly generated neurons migrated toward the injury site. These data indicate that the adult SCZ maintains a neurogenic potential that could contribute to recovery in the brain in response to the injury-induced upregulation of neurotrophic signaling. [ABSTRACT FROM AUTHOR]

During development, elimination of excess cells through programmed cell death (PCD) is essential for the establishment and maintenance of the nervous system. In many brain regions, development and major histogenesis continue beyond postnatal stages, and therefore, signs of neurogenesis and PCD are frequently observed in these postnatal brain regions. Furthermore, some brain regions maintain neurogenic potential throughout life, and continuous genesis and PCD play critical roles in sculpting these adult neural circuits. Although similar regulatory mechanisms that control PCD during development appear to also control PCD in the adult brain, adult-generated neurons must integrate into mature neural circuits for their survival. This novel requirement appears to result in unique features of PCD in the adult brain. In this article, we summarize recent findings related to PCD in the early postnatal and adult brain in rodents. [ABSTRACT FROM AUTHOR]

Bone morphogenetic protein-2 (BMP-2) induces bone regeneration in a dose-dependent manner, with higher doses of BMP-2 inducing greater bone formation. Previously, we showed that long-term delivery of BMP-2 provides better ectopic bone formation than short-term delivery of an equivalent dose. In the present study, we investigated the efficacy of orthotopic bone formation over a range of BMP-2 doses, using different delivery modes. Heparin-conjugated poly(lactic-co-glycolic acid) nanospheres suspended in fibrin gel were used as a long-term delivery system, and fibrin gel was used as a short-term delivery system. Different doses of BMP-2 were delivered to mouse calvarial defects using either long-term or short-term delivery systems. Eight weeks after treatment, bone regeneration was evaluated by histomorphometry. For both delivery systems, bone regeneration increased as the BMP-2 dose increased up to 1 µg and did not increase beyond this dose. Importantly, at BMP-2 doses higher than 1 µg, long-term delivery resulted in much greater bone formation than short-term delivery. This study shows that long-term delivery of BMP-2 is more effective at enhancing orthotopic bone formation than short-term delivery over a range of doses. [ABSTRACT FROM AUTHOR]

Bone marrow‐derived osteogenic cells can regenerate bone tissuesin vivo. The aim of the present study is to determine whether the cotransplantation of bone marrow‐derived endothelial‐like cells (BMECs) enhances bone regeneration by bone marrow‐derived osteogenic cell (BMOC) transplantation in osseous defects. Canine bone marrow cells were differentiated separately into BMECs and BMOCs. Using apatite‐coated poly(lactide‐co‐glycolide)/hydroxyapatite composite scaffolds as cell delivery vehicles, BMOCs were transplanted with or without BMECs into critical‐sized calvarial defects in immunodeficient mice. Histological analyses, microcomputed tomography, and soft X‐ray were performed to assess mineralized bone formation at 8 weeks. Cotransplantation of BMECs and BMOCs resulted in greater bone formation than transplantation of BMOCs alone. There was a significant (p < 0.05) increase in bone formation area following cotransplantation (30.8% ± 2.5%), compared with transplantation of BMOCs alone (15.3% ± 1.9%). These results demonstrate that the cotransplantation of BMECs enhances bone regeneration mediated by BMOC transplantation in osseous defects. © 2009 Wiley Periodicals, Inc. J Biomed Mater Res, 2010 [ABSTRACT FROM AUTHOR]

A considerable number of new neurons are generated daily in the dentate gyrus (DG) of the adult hippocampus, but only a subset of these survive, as many adult-generated neurons undergo programmed cell death (PCD). However, the significance of PCD in the adult brain for the functionality of DG circuits is not known. Here, we examined the electrophysiological and behavioral characteristics of Bax-knockout ( Bax-KO) mice in which PCD of post-mitotic neurons is prevented. The continuous increase in DG cell numbers in Bax-KO mice resulted in the readjustment of afferent and efferent synaptic connections, represented by age-dependent reductions in the dendritic arborization of DG neurons and in the synaptic contact ratio of mossy fibers with CA3 dendritic spines. These neuroanatomical changes were associated with reductions in synaptic transmission and reduced performance in a contextual fear memory task in 6-month-old Bax-KO mice. These results suggest that the elimination of excess DG neurons via Bax-dependent PCD in the adult brain is required for the normal organization and function of the hippocampus. [ABSTRACT FROM AUTHOR]

Beta-thymosins (Tβs) are polypeptides abundant in the cytosol, nucleus, and extracellular space of many cell types. In the nervous system, the expression of Tβs is regulated during the development of the central nervous system and following neuronal insults in cell-type and brain-region dependent manners, which may be related to the function of Tβs in the growth and regeneration of the nervous system. Supporting such a proposition, overexpression of Tβs in neurons has been shown to modify the axonal branches in vivo and neurite branches in vitro. These neurite-modifying functions have been suggested to be due to the activity of Tβs to bind actin. In addition, we recently observed that Tβs suppressed the apoptotic neuronal death in chick embryos, and these functions might be mediated by the extracellularly secreted form(s) of Tβs. These results suggest that Tβs play neurotrophic roles in the neuroprotection and neuronal growth/regeneration via their cytosolic actin-remodeling activity and extracellular antiapoptotic activity. Even though further verification is required, we also observed that Tβ15 was translocated into the injured neuronal nuclei, and this event appeared to be an eliminatory process of the injured cells. Therefore, treatment with Tβs or their related peptides appear to be beneficial for neuronal diseases by preventing neuronal death or promoting neuronal regeneration. [ABSTRACT FROM AUTHOR]

Nerve injury-induced neuronal death may occur after accidental trauma or nerve inflammation. Although the response to facial root avulsion has been examined in rodent models, there are conflicting results as to whether motoneuron (MN) death is mediated by apoptosis or necrosis. We examined the response of MNs and proximal nerves after facial nerve avulsion in adult mice. Following facial nerve avulsion in 4–5-week-old mice, we observed a progressive reduction of MNs such that by 4 weeks less than 10% of avulsed MNs remained compared with the control side. The profile of MN degeneration was distinct from axotomy-induced responses. For example, the onset of MN death was more rapid, and the extent of MN loss was greater compared with axotomy. Furthermore, the degeneration of oligodendrocytes and the activation of microglia were increased in the proximal nerve after avulsion. Ultrastructural observations suggested that root avulsion mainly induces non-apoptotic neuronal death, although a small subset of neurons appeared to die via apoptosis. To evaluate the contribution of apoptotic death, we evaluated MN responses in Bax-knockout (KO) mice in which neurons are rescued from apoptotic death. Surprisingly, although the majority of Bax-KO mice exhibited only a moderate MN loss after avulsion, a subset of Bax-KO mice (25%) exhibited extensive MN death and injury-induced changes in the nerve that were indistinguishable from events in wild-type littermates. These results suggest that both Bax-dependent and -independent forms of cell death are evoked by root avulsion, and that programmed cell death may be involved in triggering a robust necrotic response. [ABSTRACT FROM AUTHOR]

Using gene chip analyses, we have identified novel neuronal activity-dependent genes. Application of 25 mm KCl to mature (14-day culture) rat cortical neurons resulted in more than 1.5-fold induction of 19 genes and reduction of 42 genes among 1200 neural genes. Changes in the overall gene expression profiles appeared to be related to the reduction of excitability and induction of cellular survival signals. Among the genes identified, three transcriptional modulators [encoding Cbp/p300-interacting transactivator with ED-rich tail 2 (CITED2), CCAAT/enhancer binding protein β (C/EBPβ) and neuronal orphan receptor-1, (NOR1)] were newly identified as activity-dependent transcription factors, and two of these (CITED2 and NOR1) were found to be influenced by electroconvulsive shock (ECS). NOR1 was induced in specific brain regions by behavioral activation, such as exposure to a novel environment. Because the brain regions that exhibited the induction of these newly identified neuronal activity-dependent transcriptional modulators were distinct from those showing the induction of previously identified activity-dependent genes such as c -fos, these genes might be useful markers for mapping neuronal activity in vivo. [ABSTRACT FROM AUTHOR]

In neuronal development, dendritic outgrowth and arborization are important for the establishment of neural circuit formation. A previous study reported that PSD-95-interacting regulator of spine morphogenesis (Preso) formed a complex with PAK-interacting exchange factor-beta (βPix) via PSD-95/Dlg/ZO-1 (PDZ) interaction. Here, we report that Preso and its binding protein, βPix, are localized in dendritic growth cones. Knockdown and dominant-negative inhibition of Preso in cultured neurons markedly reduced the dendritic outgrowth but not branching, and led to a decrease in the intensity of βPix and F-actin in neuronal dendritic tips. Moreover, phosphatidylinositol 4,5-bisphosphate (PIP(2) ) induced a conformational change in Preso toward the open PDZ domain and enhanced the interaction with βPix. In addition, the Preso band 4.1 protein, ezrin, radixin and moesin (FERM) domain mutant is unable to interact with PIP(2) and it did not rescue the Preso-knockdown effect. These results indicate that PIP(2) is a key signalling molecule that regulates dendritic outgrowth through activation of small GTPase signalling via interaction between Preso and βPix., (© 2012 The Authors. European Journal of Neuroscience © 2012 Federation of European Neuroscience Societies and Blackwell Publishing Ltd.)

Bone morphogenetic protein-2 (BMP-2) induces bone regeneration in a dose-dependent manner, with higher doses of BMP-2 inducing greater bone formation. Previously, we showed that long-term delivery of BMP-2 provides better ectopic bone formation than short-term delivery of an equivalent dose. In the present study, we investigated the efficacy of orthotopic bone formation over a range of BMP-2 doses, using different delivery modes. Heparin-conjugated poly(lactic-co-glycolic acid) nanospheres suspended in fibrin gel were used as a long-term delivery system, and fibrin gel was used as a short-term delivery system. Different doses of BMP-2 were delivered to mouse calvarial defects using either long-term or short-term delivery systems. Eight weeks after treatment, bone regeneration was evaluated by histomorphometry. For both delivery systems, bone regeneration increased as the BMP-2 dose increased up to 1 µg and did not increase beyond this dose. Importantly, at BMP-2 doses higher than 1 µg, long-term delivery resulted in much greater bone formation than short-term delivery. This study shows that long-term delivery of BMP-2 is more effective at enhancing orthotopic bone formation than short-term delivery over a range of doses., (© 2010, Copyright the Authors. Artificial Organs © 2010, International Center for Artificial Organs and Transplantation and Wiley Periodicals, Inc.)